The effect of prostaglandin E-2 (PGE-2) and bradykinin (BK) on the natriuretic response to acetylcholine (ACh) in indomethacin-treatled dogs was examined. It was found that renal arterial infusion of ACh in indomethacin-treated dogs receiving a simultaneous renal arterial infusion of PGE-2 produced a sustained increase in sodium excretion and renal plasma flow without a change in glomerular filtration rate (GFR) or renin secretion rate (RSR). Renal arterial infusion of ACh in indomethacin-treated dogs receiving a simultaneous renal arterial infusion of BK produced an increase then a decline in sodium excretion and renal plasma flow that was accompanied by a progressive fall in GFR and a gradual rise in RSR. The data suggest that PGE-2 restores the natriuretic response to ACh in indomethacin-treated dogs through a specific action rather than by its action as a renal vasodilator.